Synthetic and plant-derived cannabinoids hold promises for the development of medicines aimed a relieving pain and anxiety. Unfortunately, their broad action on cannabinoid receptors limits their use as they also induce severe adverse effects, such as memory impairment and psychotropic effects. Cannabinoid receptors are normally engaged by endocannabinoids, which are produced and hydrolyzed by cells. A more promising avenue to develop cannabinoid-based therapeutics devoid of adverse effects is to inhibit endocannabinoid hydrolysis, thus only locally increasing endocannabinoid levels and allied cannabinoids receptor activation. Endocannabinoid are inactivated by two well-characterized enzymes: FAAH and MGL. Specific and potent inhibitors of these enzymes have been developed. We have recently identified a novel enzymatic activity which we refer to as MGL2, as it hydrolyzes the most abundant endocannabinoid 2-arachidonoyl glycerol (2-AG). We have also identified several compounds capable of inhibiting MGL2. The work that we propose in this CEBRA grant aims at: 1. Purifying MGL2 and clone its cDNA. 2. Further develop MGL2 inhibitors. Our long-term goal is to develop pharmacological and genetic tools capable of selectively inhibiting endocannabinoid hydrolysis to favor the therapeutic properties of endocannabinoids, while avoiding the adverse effects produced by cannabinoid drugs. [unreadable] [unreadable] [unreadable]